Abstract A role for T cells in the control of Mycobacterium tuberculosis (Mtb) is well established, that for B cells and humoral immunity, however, is less well understood. Emerging evidence indicate B cells and immunoglobulins (Igs) can modulate the immune response to Mtb in hosts such as humans, non-human primates (NHP), and mice. In humans, antibodies (Ab) has been shown to modulate disease outcome and/or confer protection. We have shown that ?S-/- mice, which lack secreted IgM, are more susceptible to Mtb compared to wild-type (WT) C57BL/6. The susceptibility phenotype manifests as enhanced mortality and tissue bacterial loads in the chronic phase of infection. ?S-/- mice also exhibit germinal center (GC) defects characterized by histological abnormality, decreased levels of plasma cells/plasmablasts, and an impaired GC B cell and antigen (Ag)- specific IgG response beginning in the acute phase of infection. The hypersusceptibility and GC-related phenotypes can be ameliorated by therapy with immune serum procured from Mtb-infected WT mice. We have observed enhanced Mtb susceptibility in two knockout mouse strains defective in GC B cells and follicular helper T cells (Tfh), two major cellular components of GC, supporting a role for GC in defense against Mtb. The ?S-/- data thus suggest that in the acute phase of infection, IgM plays an important role in the development of an optimal GC reaction that is required, at least in part, for establishing effective adaptive immunity for the control of chronic TB. We recently observed that the levels of lung CD4+ T cells and Th1 cells are increased in the hypersusceptible ?S-/- mice relative to WT animals during infection. As functionally distinct Th1 subsets (defined by differential expression of PD1 and KLRG1) that can be protective or detrimental to a tuberculous host have recently been described, the seemingly paradoxical ?S-/- T cell phenotype warrants further characterization, particularly in the context of the newly described Th1 subsets. IgM can mediate antimicrobial activities by modulating opsonization, dendritic cell functions, T cell immunity and humoral responses. Both natural and immune IgMs play a protective role against a variety of pathogens including intracellular bacteria. Of note, we have detected Mtb Ag-specific IgM in the circulation of both na?ve and infected mice and macaques. Mtb-specific IgM is also present in brochoalveolar lavage fluids (BALF) of uninfected and infected monkeys, suggesting that natural and immune IgM may both play a role in regulating anti-TB immunity, possible beginning in the early innate phase of Mtb-host interaction. Based on the above, we posit that: (i) IgM plays a role in optimizing the immune response to Mtb, possibly at the very early phase of infection in the lungs; (ii) IgM is required for establishing an optimal GC reaction that is required for the development of effective adaptive immunity for the control of chronic TB; (iii) natural IgM may play an important role in modulating the host response to Mtb. This proposal will rigorously test these hypotheses using both mouse and monkey TB models. We will use a variety of genetically altered mouse strains which lack specific Ig isotypes, together with bone marrow chimeras, serum therapy, and IgM-coated Mtb to probe the significance of natural and immune IgM in regulating TB immunity. We will also use an ex vivo macaque infection model that enables the evaluation of the effect of IgM on the interaction of Mtb with NHP alveolar macrophages. We believe the combined mouse and monkey approach will shed light on the role of IgM in defense against Mtb, provide mechanistic insights into how this Ab isotype regulates anti-tuberculous responses, and yield information to guide future work on the humoral immunity and natural resistance in TB and the design of novel interventions against the tubercle bacillus, including vaccines.